The nuclei of eukaryotic cells contain a subcompartment termed the nucleolus, which is the site of ribosome production. Ribosomes are comprised of ribosomal RNA and various protein components imported from the cytoplasm. Ribosomes are essential scaffolding and catalytic elements of the protein translation machinery found in the cytosol.
The main protein component in the nucleolus of eukaryotic cells is nucleolin. Nucleolin is an essential component of ribosome biogenesis. The carboxy-terminus of nucleolin is a glycine-rich region that contains RNA binding domains, which interact specifically with stem-loop structures typical of ribosomal RNA. The amino-terminus of nucleolin contains a binding site for histone H1, and binding of nucleolin to H1 promotes the decondensation of chromatin necessary to begin DNA transcription. Nucleolin also contains binding sites for nuclear localization sequences, and has been shown to shuttle between the nucleus and the cytoplasm. Thus, nucleolin also plays a role in importing proteins into the nucleus, and is a crucial element of ribosome biogenesis. (Lapeyre, B. et al. (1987) Proc. Natl. Acad. Sci.84:1472-1476; Erard, M. S. et al. (1988) Eur. J. Biochem. 175:525-530.) Elevated levels of autoantibodies to nucleolin are implicated in autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, and certain cases of chronic graft-versus-host disease. (Deng, J. S. et al. (1996) Mol. Biol. Rep. 23:191-195) In addition, there is a clinical correlation between disease severity and levels of autoantibodies to nucleolin. (Bell, S. A. et al. (1996) Br. J. Dermatol. 134:848-854.) Thus, overexpression of nucleolin and the mislocalization of nucleolin outside the nucleolus may mediate various autoimmune disorders.
One characteristic of Alzheimer's disease is the deposition of senile, or neuritic, plaques throughout the brains of affected individuals. These senile plaques contain .beta.A4 amyloid protein, which is produced from .beta. amyloid precursor protein (APP). Messenger RNA for APP is elevated in the brains of Alzheimer's disease patients, and nucleolin has been shown to bind and stabilize APP MRNA, increasing the message's half-life and thereby increasing the level of APP. Thus, nucleolin regulates APP expression, and therefore is involved in overproduction of .beta.A4 amyloid protein and the deposition of senile plaques in Alzheimer's disease. (Zaidi, S. H. E. and Malter, J. S. (1995) J Biol Chem 270:17292-17298.)
The discovery of a new human nucleolin-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of cancer, autoimmune disorders, and Alzheimer's disease.